Novel glycopeptide derivatives

ABSTRACT

Novel glycopeptide antibiotics of formula (I) can be prepared from the glycopeptide antibiotics vancomycin, A51568A, A51568B, M43A and M43D by reaction with a ketone or aldehyde followed, if appropriate, by reduction. The new glycopeptide derivatives are useful antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of application Ser. No.726,731, filed Apr. 25, 1985 now abandoned.

SUMMARY OF THE INVENTION

This invention relates to new glycopeptide derivatives of formula (I)which have useful anti-bacterial activity and to methods for preparingthese compounds from the glycopeptide antibiotics vancomycin, A51568A,A51568B, M43A and M43D.

This invention also relates to pharmaceutical formulations containingthe formula (I) compounds and to methods of using these compounds asantibacterial agents.

DETAILED DESCRIPTION OF THE INVENTION

New, improved antibiotics are continually in demand, particularly forthe treatment of human diseases. Increased potency, expanded spectrum ofbacterial inhibition, increased in vivo efficacy, and improvedpharmaceutical properties (such as greater oral absorption, higher bloodor tissue concentrations, longer in vivo half life, and moreadvantageous rate or route of excretion and rate or pattern ofmetabolism) are some of the goals for improved antibiotics.

In the search for new antibiotics, structural modification of knownantibiotics is attempted whenever possible Many antibiotics, includingthe glycopeptides, however, have such complex structures that even smallchanges are difficult to make. Furthermore, it is difficult to predictthe effect these changes will make in the desired activity. Processesfor modifying known antibiotics and the new active derivatives made bysuch processes continue, therefore, to be of great importance.

The compounds of the invention are new members of the glycopeptide groupof antibiotics. The compounds can be prepared from the knownglycopeptides vancomycin (see, for example, U.S. Pat. No. 3,067,099),antibiotic A51568 factor A (see U.S. Pat. No. 4,495,179) and A51568factor B (see U.S. Pat. No. 4,558,008); antibiotic M43A (see U.S. Pat.No. 4,548,925) and antibiotic M43D (see U.S. Pat. No. 4,547,488).

The compounds of this invention have general formula (I): ##STR1##wherein R is hydrogen or methyl;

n is 1 or 2; and

(i) R₁ is hydrogen or methyl;

R₂ and R₃, independently, are hydrogen or a group of the formula: R₆ R₇CH--;

R₆ and R₇ are independently R₅, R₅ --(C₁ -C₅ -alkyl) or R₅ --(C₂ -C₅-alkenyl);

R₅ is hydrogen, C₁ -C₁₀ -alkyl, C₂ -C₁₀ -alkenyl, C₁ -C₄ alkoxy, C₃ -C₁₀-cycloalkyl, C₅ -C₁₂ -cycloalkenyl, phenyl, napththyl, indenyl,tetralinyl, decalinyl, adamantyl, a monocyclic heterocyclic ring systemcomprising 3 to 8 atoms in the ring or a bicyclic heterocyclic ringsystem comprising 6 to 11 atoms, provided that at least one atom of thering system is carbon and at least one atom of the ring system is aheteroatom selected from O, N and S, and R₅ may be substituted with oneor more hydroxy, nitro, C₁ -C₁₀ -alkoxy, C₁ -C₁₀ -alkyl, phenyl, C₁ -C₆-alkylthio, nitrile, halo, C₂ -C₄ -acylamino, amino, C₁ -C₄-dialkylamino groups; and R₄ is hydrogen; or

(ii) R₁ and R₂ and/or R₃ and R₄ together form a group of the formula##STR2## provided that: (1) at least one of R₂ and R₃ must be other thanhydrogen; (2) when n is 2, R must be hydrogen; (3) when R is methyl andR₃ is hydrogen, R₂ cannot be methyl and (4) when R and R₁ are bothmethyl, then R₂ is hydrogen or methyl and n is 1;

and salts of these compounds.

One group of compounds of this invention have formula 1: ##STR3##wherein R is hydrogen or methyl;

R₁ is hydrogen;

R₂ and R₃, independently, are hydrogen, R₅ --(C₁ -C₆)-alkyl or R₅ --(C₂-C₆ -alkenyl); and R₄ is hydrogen; or

R₁ and R₂ or R₃ and R₄ together form an R₅ --(C₁ -C₆ alkylidenyl) or R₅--(C₂ -C₆ -alkenylidenyl) group;

R₅ is C₁ -C₁₀ -alkyl, C₂ -C₁₀ -alkenyl, C₃ -C₁₀ -cycloalkyl, C₅ -C₁₂-cycloalkenyl, phenyl, napththyl, indenyl, tetralinyl, decalinyl,adamantyl, a monocyclic heterocyclic ring system comprising 3 to 8 atomsin the ring or a bicyclic heterocyclic ring system comprising 6 to 11atoms, provided that at least one atom of the ring system is carbon andat least one atom of the ring system is a heteroatom selected from O, Nand S, and wherein R₅ may be substituted with one or more hydroxy, C₁-C₆ -alkoxy, C₁ -C₆ -alkylthio, halo or amino groups; and

n=1 or 2;

provided that: (1) at least one of R₂ and R₃ must be other thanhydrogen; and (2) when n is 2, R must be hydrogen;

and the salts of these compounds.

Formula (I) compounds in which R₂ is an R₆ R₇ CH-- group and R₃ ishydrogen are preferred.

A second group of compounds of this invention have formula 2: ##STR4##wherein R_(2a) is hydrogen or methyl;

R_(3a) is R₅ --(C₁ -C₆ -alkyl) or R₅ --(C₂ -C₆ -alkenyl); and

R_(4a) is hydrogen; or

R_(3a) and R_(4a) together form an R₅ --(C₁ -C₆ -alkylidenyl) or R₅--(C₂ -C₆ -alkenylidenyl) group and salts of these compounds.

The compounds of the invention can be prepared by reacting vancomycin,antibiotic A51568 factor A, A51568 factor B, M43A or M43D, which havethe following structural formulas

    __________________________________________________________________________     ##STR5##                                                                                             ##STR6##                                                                      ##STR7##                                              Compound           R.sub.b                                                                          R.sub.1b       R.sub.2b                                                                         n                                     __________________________________________________________________________    Vancomycin         CH.sub.3                                                                         H              H  1                                     M43A               CH.sub.3                                                                         CH.sub.3       CH.sub.3                                                                         1                                     M43D               CH.sub.3                                                                         CH.sub.3       H  1                                     A51568A            H  H              H  1                                     A51568B            H  H              H  2                                     __________________________________________________________________________

with a ketone or aldehyde of formula: ##STR8## so as to form alkylideneor alkenylidene derivatives of the invention, optionally followed byreduction so as to form alkyl or alkenyl derivatives.

The reaction with the R⁶ R⁷ CO compound is preferably carried out attemperatures between 25° and 100° C., preferably from 25° to 70° C.,utilizing a polar aprotic solvent such as dimethylformamide.

The reduction of the Schiff's base thus formed can be effected using achemical reducing agent such as a metal borohydride, for example sodiumcyanoborohydride. Once again an aprotic solvent such asdimethylformamide is preferred and the reduction can be effected usingtemperatures in the range from 25° to 100° C., preferably about 70° C.

It will be appreciated that the sugar groups in the above formulae havethe same configuration as do those in vancomycin, i.e.,α-O-vancosaminyl-β-O-glucosyl.

Each R₆ and R₇ group may have from 1 to 15 carbon atoms, and preferablythe sum of the carbon atoms in R₆ and R₇ is no greater than 15. Thosecompounds wherein either R₁ and R₂ or R₃ and R₄ together form an R₅--(C₁ -C₆ -alkylidenyl) or R₅ --(C₂ -C₆ -alkenylidenyl) group are knownas Schiff bases.

The terms "C₁ -C₅ -alkyl", "C₁ -C₆ -alkyl" and "C₁ -C₁₀ -alkyl" refer toa saturated, straght- or branched-chain alkyl group containing thespecified number of carbon atoms. The terms "C₂ -C₅ -alkenyl", "C₂ -C₆-alkenyl" and "C₂ -C₁₀ -alkenyl" refer to an unsaturated straight orbranched-chain alkenyl group containing the specified number of carbonatoms. Those compounds wherein R₂ or R₃ is R₅ --(C₁ -C₆ -alkyl) or R₅--(C₂ -C₆ -alkenyl), referred to herein as "reduced Schiff bases", areprepared by reduction of the corresponding compounds wherein either R₁and R₂ or R₃ and R₄ represent an R₅ --(C₁ -C₆ -alkylidenyl) or R₅ -(C₂-C₆ -alkenylidenyl) group.

Methoxy, ethoxy and tert-butoxy are typical C₁ -C₆ -alkoxy groups.Methylthio, n-propylthio and isopentylthio are typical C₁ -C₆ -alkylthiogroups. Halo substituents are selected from the group consisting ofchloro, bromo, fluoro and iodo. Cyclopropyl, cycloheptyl andcyclohexadienyl are examples of C₃ -C₁₀ -cycloalkyl and C₅ -C₁₂-cycloalkenyl groups.

The formula 1 compounds can be prepared from the antibiotics vancomycin,A51568A and A51568B. The formula 2 compounds can be prepared from theantibiotics M43A and M43D.

The compounds of the invention are shown as zwitterions. Those in theart will recognize, however, that each has a carboxyl group, one or twoamino groups and three phenolic groups which can react to form varioussalts. All such forms of the compounds are part of this invention. Thesalts are useful, for example, for separating and purifying theantiobiotics. In addition, the salts have an improved solubility inwater.

The salts are prepared using standard procedures for salt preparation.For example, the zwitterion can be neutralized with an appropriate acidto form an acid addition salt.

The acid addition salts are particularly useful. Representative suitablesalts include those salts formed by standard reactions with both organicand inorganic acids such as, for example, sulfuric, hydrochloric,phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, cholic,pamoic, mucic, D-glutamic, d-camphoric, glutaric, glycolic, phthalic,tartaric, formic, lauric, stearic, salicylic, methanesulfonic,benzenesulfonic, sorbic, picric, benzoic, cinnamic and like acids.

Pharmaceutically acceptable acid addition salts are an especiallypreferred group of salts of this invention.

This invention further relates to processes for preparing the compoundsof the invention from the glycopeptide antibiotics vancomycin, A51568A,A51568B, M43A and M43D. For convenience in discussing the processes ofthis invention, the following subgroups are designated:

    ______________________________________                                        Com-                                                                          pounds                                                                              Definition                                                              ______________________________________                                        1a    1 compounds wherein R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4                together form an R.sub.5 --(C.sub.1 --C.sub.6 --alkylidenyl) or               R.sub.5 --(C.sub.2 --C.sub.6 --alkenylidenyl) group                     1b    1 compounds wherein R.sub.2 or R.sub.3 is R.sub.5 --(C.sub.1                  --C.sub.6 --alkyl) or R.sub.5 --(C.sub.2 --C.sub.6 --alkenyl)           2a    2 compounds wherein R.sub.3a and R.sub.4a together form                       an R.sub.5 --(C.sub.1 --C.sub.6 --alkylidenyl) or                             R.sub.5 --(C.sub.2 --C.sub.6 --alkenyli-                                      denyl) group                                                            2b    2 compounds wherein R.sub.3a is R.sub.5 --(C.sub.1 --C.sub.6                  --alkyl) or                                                                   R.sub.5 --(C.sub.2 --C.sub.6 --alkenyl)                                 ______________________________________                                    

In one aspect, this invention provides a process for preparing a formula1a compound which comprises reacting vancomycin, A51568A or A51568B withthe corresponding ##STR9## aldehyde or ketone wherein R₆ and R₇ are asdefined, supra, preferably, in a polar aprotic solvent until the 1acompound is formed. A preferred temperature range for this process isfrom about 25° to about 70° C., and a preferred time is from about 3 toabout 18 hours.

In a second aspect, this invention provides a process for preparing aformula 1b compound which comprises reacting the corresponding formula1a compound with a reducing agent to reduce the R₆ R₇ C═N-- doublebond(s) in the 1a compound. A preferred reducing agent for this processis a borohydride such as, for example, sodium cyanoborohydride.

In another aspect, this invention provides a process for preparing aformula 2a compound which comprises reacting M43A or M43D with thecorresponding ##STR10## aldehyde or ketone in a polar aprotic solventunit the 2a compound is formed. A preferred temperature range for thisprocess is from about 25° to about 70° C., and a preferred time is fromabout 2 to about 18 hours.

In yet another aspect, this invention provides a process for preparing aformula 2b compound which comprises reacting the corresponding formula2a compound with a reducing agent to reduce the R₆ R₇ C═N--double bondin the formula 2a compound. A preferred reducing agent for this processis a borohydride such as, for example, sodium cyanoborohydride.

When preparing those formula 1b and 2b compounds wherein the R₂, R₃, orR_(3a) group contains a --C═C-- group, the reducing agent used should beone which selectively reduces the R₆ R₇ C═N-- group only. Sodiumborohydride is an example of such a selective reducing agent.

The compounds of this invention are useful antibacterial agents. Theformula 1b and 2b compounds are preferred for this purpose.

The formula 1b compounds wherein R₂ is hydrogen and R₃ is an R₅ --(C₁-C₆ -alkyl) or R₅ --(C₂ -C₆ -alkenyl) group are especially useful.Within this group, those compounds wherein the R₃ moiety contains fromeight to twelve carbon atoms are particularly beneficial.

The formula 1b compounds wherein R is methyl, R₂ is hydrogen and R₃ isan R₅ --(C₁ -C₆ -alkyl or R₅ --(C₂ -C₆ -alkenyl) group are more readilyand inexpensively prepared since the starting material, vancomycin, is acommercial product.

Another useful group of formula 1b compounds are those wherein R₃ ishydrogen and R₂ is an R₅ --(C₁ -C₆ -alkyl) or R₅ --(C₂ -C₆ -alkenyl)group. Preferred compounds within this group are those wherein the R₂moiety contains from five to fourteen carbon atoms. Economicallypreferably compounds within this group are those wherein R is methyl(the compounds prepared from vancomycin).

Yet another group of formula 1b compounds are those wherein R₂ and R₃are both R₅ --(C₁ -C₆ -alkyl) or R₅ --(C₂ -C₆ -alkenyl) groups. Again,the most preferred compounds of this subgroup are those wherein R ismethyl.

Illustrative compounds of this invention are listed in Tables I-IV.

                  TABLE I                                                         ______________________________________                                        Illustrative Formula 1b Compounds.sup.a                                       Compound                                                                      No.     R      R.sub.2       R.sub.3                                          ______________________________________                                         1      Me     H             n-dodecyl                                         2      Me     H             n-decyl                                           3      Me     n-decyl       H                                                 4      Me     n-decyl       n-decyl                                           5      Me     H             n-nonyl                                           6      Me     n-nonyl       n-nonyl                                           7      Me     H             n-octyl                                           8      Me     n-octyl       H                                                 9      Me     n-octyl       n-octyl                                          10      Me     H             n-heptyl                                         11      Me     n-heptyl      H                                                12      Me     n-heptyl      n-heptyl                                         13      Me     H             n-hexyl                                          14      Me     n-hexyl       H                                                15      Me     H             n-pentyl                                         16      Me     n-pentyl      H                                                17      Me     H             n-butyl                                          18      Me     n-butyl       H                                                19      Me     n-butyl       n-butyl                                          20      Me     H             n-propyl                                         21      Me     n-propyl      H                                                22      Me     n-propyl      n-propyl                                         23      Me     Et            H                                                24      Me     Et            Et                                               25      H      n-decyl       H                                                26      H      H             n-decyl                                          27      H      isooctyl      H                                                28      Me     Me            Me                                               29      Me     isopropyl     isopropyl                                        30      Me     H             isopropyl                                        31      Me     H             5-hydroxy-n-pentyl                               32      Me     5-hydroxy-n-pentyl                                                                          H                                                33      Me     "             5-hydroxy-n-pentyl                               34      Me     H             6-bromo-n-hexyl                                  35      Me     6-bromo-n-hexyl                                                                             H                                                36      Me     H             3-ethoxy-n-propyl                                37      Me     3-ethoxy-n-propyl                                                                           H                                                38      Me     3-ethoxy-n-propyl                                                                           3-ethoxy-n-propyl                                39      Me     H             benzyl                                           40      Me     benzyl        H                                                41      Me     benzyl        benzyl                                           42      H      H             benzyl                                           43      Me     H             3-phenyl-n-(prop-2-enyl)                         44      Me     3-phenyl-n-   H                                                               (prop-2-enyl)                                                  45      Me     H             3-phenyl-n-propyl                                46      Me     H             (pyrid-3-yl)methyl                               47      Me     (pyrid-2-yl)methyl                                                                          H                                                48      Me     H             (2-amino-thiazol-                                                             4-yl)ethyl                                       49      H      H             phenethyl                                        50      Me     H             (indol-3-yl)methyl                               51      Me     H             (adamant-1-yl)methyl                             52      Me     H             n-undecyl                                        53      Me     H             3-(methylthio)-n-propyl                          54      Me     3-(methylthio)-                                                                             H                                                               n-propyl                                                       ______________________________________                                         .sup.a In these compounds, n = 1 and R.sub.4 = H                         

                  TABLE II                                                        ______________________________________                                        Illustrative Formula 1a Compounds wherein                                     R.sub.1 --R.sub.2 = Alkylidenyl or Alkenylidenyl.sup.a                        Compound                                                                      No.        R      R.sub.1 --R.sub.2 Group                                     ______________________________________                                        55         Me     n-decylidenyl                                               56         Me     n-nonylidenyl                                               57         Me     n-octylidenyl                                               58         Me     n-heptylidenyl                                              59         Me     n-hexylidenyl                                               60         Me     n-pentylidenyl                                              61         Me     n-butylidenyl                                               62         Me     n-propylidenyl                                              63         Me     ethylidenyl                                                 64         H      n-decylidenyl                                               65         Me     isopropylidenyl                                             66         Me     5-hydroxy-n-pentylidenyl                                    67         Me     6-bromo-n-hexylidenyl                                       68         Me     3-ethoxy-n-propylidenyl                                     69         Me     benzylidenyl                                                70         Me     3-phenyl-n-(prop-2-enylidenyl)                              71         Me     3-phenyl-n-propylidenyl                                     72         Me     (pyrid-4-yl)methylidenyl                                    73         Me     (2-amino-thiazol-4-yl)ethylidenyl                           74         Me     phenethylidenyl                                             75         Me     (indol-3-yl)methylidenyl                                    76         Me     (adamant-1-yl)methylidenyl                                  77         Me     3-(methylthio)-n-propylidenyl                               78         Me     n-undecylidenyl                                             ______________________________________                                         .sup.a In these compounds, n = 1 and R.sub.3 and R.sub.4 = H             

                  TABLE III                                                       ______________________________________                                        Illustrative Formula 1a Compounds wherein R.sub.1 --R.sub.2                   and R.sub.3 --R.sub.4 = Alkylidenyl or Alkenylidenyl.sup.a                    Cmpd.                                                                         No.      R       R.sub.1 --R.sub.2 Group                                                                    R.sub.3 --R.sub.4 Group                         ______________________________________                                        79       Me      n-decylidenyl                                                                              n-decylidenyl                                   80       Me      n-nonylidenyl                                                                              n-nonylidenyl                                   81       Me      n-octylidenyl                                                                              n-octylidenyl                                   82       Me      n-heptylidenyl                                                                             n-heptylidenyl                                  83       Me      n-butylidenyl                                                                              n-butylidenyl                                   84       Me      n-propylidenyl                                                                             n-propylidenyl                                  85       Me      ethylidenyl  ethylidenyl                                     86       H       n-decylidenyl                                                                              n-decylidenyl                                   87       Me      isopropylidenyl                                                                            isopropylidenyl                                 88       Me      5-hydroxy-n- 5-hydroxy-n-                                                     pentylidenyl pentylidenyl                                    89       Me      6-bromo-n-   6-bromo-n-                                                       hexylidenyl  hexylidenyl                                     90       Me      3-ethoxy-n-  3-ethoxy-n-                                                      propylidenyl propylidenyl                                    91       Me      benzylidenyl benzylidenyl                                    92       Me      3-phenyl-n-(prop-                                                                          3-phenyl-n-(prop-                                                2-enylidenyl)                                                                              2-enylidenyl)                                   93       Me      3-phenyl-n-  3-phenyl-n-                                                      propylidenyl propylidenyl                                    94       Me      (pyrid-4-yl)-                                                                              (pyrid-4-yl)-                                                    methylidenyl methylidenyl                                    95       Me      (2-aminothiazol-4-                                                                         (2-aminothiazol-4-                                               yl)ethylidenyl                                                                             yl)ethylidenyl                                  96       Me      phenethylidenyl                                                                            phenethylidenyl                                 97       Me      (indol-3-yl)-                                                                              (indol-3-yl)-                                                    methylidenyl methylidenyl                                    98       Me      (adamant-1-yl)-                                                                            (adamant-1-yl)-                                                  methylidenyl methylidenyl                                    ______________________________________                                         .sup.a In these compounds, n = 1                                         

                  TABLE IV                                                        ______________________________________                                        Illustrative Formula 1a Compounds wherein                                     R.sub.3 and R.sub.4 = Alkylidenyl or Alkenylidenyl.sup.a                      Compound                                                                      No.        R      R.sub.3 --R.sub.4 Group                                     ______________________________________                                         99        Me     n-dodecylidenyl                                             100        Me     n-decylidenyl                                               101        Me     n-nonylidenyl                                               102        Me     n-octylidenyl                                               103        Me     n-heptylidenyl                                              104        Me     n-hexylidenyl                                               105        Me     n-pentylidenyl                                              106        Me     n-butylidenyl                                               107        Me     n-propylidenyl                                              108        Me     ethylidenyl                                                 109        H      n-decylidenyl                                               110        Me     isopentylidenyl                                             111        Me     5-hydroxy-n-pentylidenyl                                    112        Me     6-bromo-n-hexylidenyl                                       113        Me     3-ethoxy-n-propylidenyl                                     114        Me     benzylidenyl                                                115        Me     3-phenyl-n-(prop-2-enylidenyl)                              116        Me     3-phenyl-n-propylidenyl                                     117        Me     (pyrid-4-yl)methylidenyl                                    118        Me     (2-amino-thiazol-4-yl)ethylidenyl                           119        Me     phenethylidenyl                                             120        Me     (indol-3-yl)methylidenyl                                    121        Me     (adamant-1-yl)methylidenyl                                  122        Me     n-undecylidenyl                                             123        Me     3-(methylthio)-n-propylidenyl                               ______________________________________                                         .sup.a In these compounds, n = 1 and R.sub.2 = H                         

Illustrative formula 2 compounds of this invention are listed in TablesV and VI.

                  TABLE V                                                         ______________________________________                                        Illustrative Formula 2b Compounds                                             Compound                                                                      No.          R.sub.2a                                                                             R.sub.3a                                                  ______________________________________                                        124          Me     n-decyl                                                   125          H      n-decyl                                                   126          Me     n-hexadecyl                                               127          Me     isooctyl                                                  128          Me     n-butyl                                                   129          Me     benzyl                                                    130          Me     5-hydroxypentyl                                           131          Me     3-(methylthio)-n-propyl                                   132          Me     3-phenyl-n-(prop-2-enyl)                                  133          H      (pyrid-3-yl)methyl                                        134          Me     benzyl                                                    ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                        Illustrative Formula 2a Compounds                                             Compound                                                                      No.         R      R.sub.3a --R.sub.4a Group                                  ______________________________________                                        135         Me     n-decylidenyl                                              136         H      n-decylidenyl                                              137         Me     n-hexadecylidenyl                                          138         Me     isooctylidenyl                                             139         Me     n-butylidenyl                                              140         Me     benzylidenyl                                               141         Me     5-hydroxy-n-pentylidenyl                                   142         Me     3-(methylthio)-n-propylidenyl                              143         Me     3-phenyl-n-(prop-2-enylidenyl)                             144         H      (pyrid-3-yl)methylidenyl                                   145         Me     benzylidenyl                                               ______________________________________                                    

The formula (I) compounds inhibit the growth of a broad spectrum ofpathogenic bacteria, especially Gram-positive bacteria. Tables VII andVIII summarize the minimal inhibitory concentrations (MIC's) at whichthe compounds inhibit certain organisms, as determined by standardagar-dilution assays.

    TABLE VII      In Vitro Activity of Formula (I) Compounds  MIC (mcg/ml) Organism     Compound Number.sup.a        1 2 3 4 5 6 7 8 9 10       Staphylococcus aureus NRRL B313 0.25 0.125 0.5 2 0.25 1 0.25 0.5 1     0.25 Staphylococcus aureus V41 0.25 0.25 0.5 4 0.25 1 0.25 0.5 1 0.5     Staphylococcus aureus X400 0.25 0.25 0.5 4 0.25 1 0.25 1 1 0.5 Staphyloco     ccus aureus S13E 0.25 0.25 0.5 4 0.25 2 0.25 1 1 0.5 Staphylococcus     epidermidis EPI1 0.5 0.25 2 16 0.5 4 1 2 4 2 Staphylococcus epidermidis     222 0.125 0.25 1 4 0.25 2 0.5 1 2 1 Streptococcus pyogenes C203 0.125     0.06 0.5 2 0.125 1 0.125 0.5 0.5 0.5 Streptococcus pneumoniae Park 1     0.25 0.125 0.5 4 0.25 2 0.125 1 1 0.125 Streptococcus faecium ATCC 9790     0.25 0.25 0.5 4 0.25 1 0.25 1 1 0.5 Streptococcus sp. group D 2041 0.125     0.25 1 4 0.5 2 0.5 2 2 1 Haemophilus influenzae C.L. >128 128 128 >128     64 >128 32 128 >128 128 Haemophilus influenzae 76 >128 128 >128 >128 64     >128 32 128 >128 128 Escherichia coli N10 >128 >128 >128 >128 >128 >128     >128 >128 >128 >128 Escherichia coli EC14 >128 >128 >128 >128 >128 >128     >128 >128 >128 >128 Escherichia coli TEM >128 >128 >128 >128 >128 >128     >128 >128 >128 >128 Klebsiella pneumoniae X26 >128 >128 >128 >128 >128     >128 >128 >128 >128 >128 Klebsiella pneumoniae X68 >128 >128 >128 >128     >128 >128 >128 >128 >128 >128 Klebsiella pneumoniae KAE >128 >128 >128     >128 >128 >128 >128 >128 >128 >128        12 13 15 17 19 20 22 24 26 124       Staphylococcus aureus NRRL B313 0.5 0.5 0.5 1 0.5 1 2 1 0.25 0.5     Staphylococcus aureus V41 1 1 1 1 1 1 2 1 0.25 0.5 Staphylococcus aureus X     400 1 1 1 1 1 1 2 2 0.25 0.5 Staphylococcus aureus S13E 1 0.5 1 1 1 1 2     1 0.25 0.5 Staphylococcus epidermidis EPI1 2 2 2 4 2 4 4 2 0.5 1     Staphylococcus epidermidis 222 1 1 1 2 1 1 4 2 0.25 0.5 Staphylococcus     pyogenes C203 0.5 0.5 0.5 1 0.5 0.5 2 1 0.25 0.25 Streptococcus pneumonia     e Park 1 0.5 0.125 0.125 0.5 0.5 0.5 1 1 0.25 0.5 Streptococcus faecium     ATCC 9790 1 1 1 2 1 1 2 2 0.5 0.5 Streptococcus sp. group D 2041 1 1 2 4     2 1 8 4 0.5 0.5 Haemophilus influenzae C.L. >128 128 128 128 >128 128     >128 <128 128 >64 Haemophilus influenzae 76 128 128 128 128 128 128 128     128 128 >64 Escherichia coli N10 >128 >128 >128 >128 >128 >128 >128 >128     >128 >64 Escherichia coli EC14 >128 >128 >128 >128 >128 >128 >128 >128     >128 64 Escherichia coli TEM >128 >128 >128 >128 >128 >128 >128 >128     >128 >64 Klebsiella pneumoniae X26 >128 >128 >128 >128 >128 > 128 >128     >128 >128 >64 Klebsiella pneumoniae X68 >128 >128 >128 >128 >128 >128     >128 >128 >128 >64 Klebsiella pneumoniae KAE >128 >128 >128 >128 >128     >128 >128 >128 >128 >64     .sup.a Compound Numbers from Tables I-V

                                      TABLE VIII                                  __________________________________________________________________________    In Vitro Activity of Formula (I) Compounds                                                      MIC (mcg/ml)                                                                  Compound Number.sup.a                                       Organism          77    80     81    84     93    94     105                  __________________________________________________________________________    Staphylococcus aureus NRRL B313                                                                 0.25  0.25   0.06  0.125  0.5   0.25   0.5                  Staphylococcus aureus V41                                                                       0.5   0.5    0.125 0.125  1     0.5    0.5                  Staphylococcus aureus X400                                                                      0.5   0.25   0.125 0.125  1     0.5    0.5                  Staphylococcus aureus S13E                                                                      0.5   0.25   0.06  0.125  0.5   0.5    0.5                  Staphylococcus epidermidis EPI1                                                                 1     1      0.25  0.25   2     1      1                    Staphylococcus epidermidis 222                                                                  0.5   0.5    0.125 0.25   1     0.5    0.5                  Streptococcus pyogenes C203                                                                     0.25  0.25   0.06  0.06   0.25  0.25   0.5                  Streptococcus pneumoniae Park 1                                                                 0.125 0.03   0.06  0.03   0.25  0.25   0.06                 Streptococcus faecium ATCC 9790                                                                 0.5   0.25   0.06  0.125  0.25  0.25   0.5                  Streptococcus sp. group D 2041                                                                  1     1      0.25  0.25   0.5   0.25   2                    Haemophilus influenzae C.L.                                                                     128   64     32    32     >128  >128   64                   Haemophilus influenzae 76                                                                       128   64     32    64     >128  >128   64                   Escherichia coli N10                                                                            >128  >128   >128  >128   >128  >128   >128                 Escherichia coli EC14                                                                           >128  >128   >128  >128   >128  >128   >128                 Escherichia coli TEM                                                                            >128  >128   >128  >128   >128  >128   >128                 Klebsiella pneumoniae X26                                                                       >128  >128   >128  >128   >128  >128   >128                 Klebsiella pneumoniae X68                                                                       >128  >128   >128  >128   >128  >128   >128                 Klebsiella pneumoniae KAE                                                                       >128  >128   >128  >128   >128  >128   >128                 __________________________________________________________________________     .sup.a Compound Numbers = Example Numbers                                

The compounds of this invention have also shown in vivo antimicrobialactivity against experimental bacterial infections. When two doses oftest compound were administered to mice in experimental infections, theactivity observed was measured as an ED₅₀ value [effective dose in mg/kgto protect 50% of the test animals: see Warren Wick, et al., J.Bacteriol. 81, 233-235 (1961)]. ED₅₀ values observed are given in TablesIX and X.

                  TABLE IX                                                        ______________________________________                                        ED.sub.50 Values for Formula 1 Compounds.sup.a                                         ED.sub.50 (mg/kg/2)                                                           Compound Numbers.sup.b                                               Organism   1       2      3     5    7    8                                   ______________________________________                                        Staphylococcus                                                                           >5      1.8    >5    2.9  3.4  >5                                  aureus                                                                        Streptococcus                                                                            0.31    1.6    4.6   0.56 0.98 3.7                                 pyogenes                                                                      Streptococcus                                                                            0.42    0.51   3.6   0.81 0.44 3.1                                 pneumoniae                                                                    ______________________________________                                         .sup.a Administered subcutaneously                                            .sup.b Compound numbers from Table I                                     

                  TABLE X                                                         ______________________________________                                        ED.sub.50 Values for Formula (I) Compounds.sup.a                                       ED.sub.50 (mg/kg/2)                                                           Compound Numbers.sup.b                                               Organism   77    80     81   84   93   94    105                              ______________________________________                                        Staphylococcus                                                                           1.1   1.34   0.74 0.65 0.19 >0.12 0.98                             aureus                                                                        Streptococcus                                                                            0.8   0.78   1.16 0.69 0.62 0.66  1.18                             pyogenes                                                                      Streptococcus                                                                            1.2   0.41   1.26 1.14 0.23 0.2   1.25                             pneumoniae                                                                    ______________________________________                                         .sup.a Administered subcutaneously                                            .sup.b Compound numbers = Example Numbers                                

Pharmaceutical formulations of formula (I) and their pharmaceuticallyacceptable salts are also part of this invention. Thus, a formula (I)compound, preferably as a pharmaceutically acceptable salt, can beformulated for oral or parenteral administration for the therapeutic orprophylactic treatment of bacterial infections. For example, thecompound can be admixed with conventional pharmaceutical carriers andexcipients and used in the form of tablets, capsules, elixirs,suspensions, syrups, wafers and the like. The compositions comprising aformula (I) compound will contain from about 0.1 to about 90% by weightof the active compound, and more generally from about 10 to about 30%.The compositions may contain common carriers and excipients, such ascorn starch or gelatin, lactose, sucrose, microcrystalline cellulose,kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid.Disintegrators commonly used in the formulations of this inventioninclude croscarmellose sodium, microcrystalline cellulose, corn starch,sodium starch glycolate and alginic acid. Tablet binders that can beincluded are acacia, methylcellulose, sodium carboxymethylcellulose,polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose,starch and ethylcellulose. Lubricants that can be used include magnesiumstearate or other metallic stearates, stearic acid, silicone fluid,talc, waxes, oils and colloidal silica. Flavoring agents such aspeppermint, oil of wintergreen, cherry flavoring or the like can also beused. It may be desirable to add a coloring agent to make the dosageform more esthetic in appearance or to help identify the product.

For intravenous (IV) use, a water soluble form of the antibiotic can bedissolved in one of the commonly used intravenous fluids andadministered by infusion. Such fluids as, for example, physiologicalsaline, Ringer's solution or 5% dextrose solution can be used.

For intramuscular preparations, a sterile formulation of a suitablesoluble salt form of the compound, for example the hydrochloride salt,can be dissolved and administered in a pharmaceutical diluent such asWater-for-Injection, physiological saline or 5% glucose solution. Asuitable insoluble form of the compound may be prepared and administeredas a suspension in an aqueous base or a pharmaceutically acceptable oilbase, e.g. an ester of a long chain fatty acid such as ethyl oleate.

For oral use, a sterile formulation of a suitable salt form of theantibiotic, for example, the hydrochloride salt, formulated in a diluentsuch as distilled or deionized water, is particularly useful.

Alternatively, the unit dosage form of the antibiotic can be a solutionof the antibiotic or preferably a salt thereof in a suitable diluent insterile, hermetically sealed ampoules. The concentration of theantibiotic in the unit dosage may vary, e.g. from about 1 percent toabout 50 percent depending on the particular form of the antibiotic andits solubility and the dose desired by the physician.

In a further aspect, this invention provides a method for treatinginfectious diseases, especially those caused by Gram-positivemicroorganisms, in animals. The animal may be either susceptible to, orinfected with, the microorganism. The method comprises administering tothe animal an amount of a formula (I) compound or its pharmaceuticallyacceptable salt which is effective for this purpose. In general aneffective amount of a formula (I) compound is a dose between about 0.5and about 100 mg/kg. A preferred dose is from about 10 to about 60 mg/kgof active compound. A typical daily dose for an adult human is fromabout 250 mg to about 1.0 g.

In practicing this method, the antibiotic can be administered in asingle daily dose or in multiple doses per day. The treatment regime mayrequire administration over extended periods of time, e.g., for severaldays or for from two to three weeks. The amount per administered dose orthe total amount administered will depend on such factors as the natureand severity of the infection, the age and general health of thepatient, the tolerance of the patient to the antibiotic and themicroorganism or microorganisms involved in the infection.

A convenient method of practicing the treatment method is to administerthe antibiotic via IV infusion. In this procedure a sterile formulationof a suitable soluble salt of the antibiotic is incorporated in aphysiological fluid, such as 5% dextrose solution, and the resultingsolution is infused slowly IV. Alternatively, the piggy-back method ofIV infusion can also be used.

In another embodiment, this invention relates to methods of increasingfeed-utilization efficiency in poultry, swine, sheep and cattle, ofpromoting growth rates in cattle raised for meat production and ofenhancing milk production in lactating ruminants. For increasingfeed-utilization efficiency and promoting growth, a formula (I) compoundis administered orally in a suitable feed in an amount of from about 2to about 200 grams per ton of total feed. For beef cattle, for example,a range of about 12 to 3000 mg/head/day is suitable. For enhancing milkproduction in lactating ruminants, oral administration of a daily amountof from about 0.04 to about 16 mg/kg of body weight (or about 25 toabout 5000 mg/ruminant/day) is suggested.

The following examples are provided to illustrate this invention. Tosimplify discussion, "N^(van) " is used to indicate the nitrogen onvancosamine and "N^(leu) " is used to indicate the nitrogen in theleucine group. Reactions were followed by analytical high performanceliquid chromatography (HPLC) using a Water's Bondapak C₁₈ column with agradient solvent system of CH₃ CN and 0.5% triethylamine (pH 3) bufferand detecting with UV at 254 nm.

EXAMPLES 1-2 Preparation of N^(van) -(n-Decylidenyl)vancomycin (Compound100) and N^(van) -(n-Decyl)vancomycin (Compound 2)

Vancomycin free base (5 g, 3.58 mmoles) was dissolved indimethylformamide (DMF, 75 ml). n-Decyl aldehyde (0.7 ml, 3.72 mmoles)was added. The reaction mixture was stirred for 2 hours in a 70° C. oilbath to give N^(van) -(n-decylidenyl)vancomycin (Compound 100).

Sodium cyanoborohydride (275 mg, 4.4 mmoles) was added to the solutioncontaining Compound 100. The reaction mixture was stirred for another 2hours in the oil bath and then was cooled to room temperature andtransferred to a Virtis jar. Celite was added until a thick pasteformed. The paste was evaporated under vacuum overnight. The powderyresidue obtained was stirred with methanol and filtered three times. Themethanol filtrates were combined and evaporated to dryness under vacuum.The residue obtained was triturated with diethyl ether. The insolubleresidue was dissolved in methanol and filtered, and the filtrate wasevaporated to dryness under vacuum.

This product was purified by reversed-phase high performance liquidchromatography (HPLC), using a Water's Prep Pak/500 column, eluting withan acetonitrile-water gradient system and detecting with UV at 280 nm,to give 793.5 mg of N^(van) -(n-decyl)vancomycin (Compound 2). Theidentity of the product was confirmed by fast-atom-bombardment massspectrometry (FABMS).

EXAMPLES 3-73

The procedure described Examples 1-2 (with the appropriate startingaldehyde) was used to prepare mono-N^(van) -, mono-N^(leu) - anddi-N^(van), N^(leu) derivatives. In general, the smaller the group to beadded, the more complex the crude product and the more difficult theisolation. Generally, the major product is the N^(van) derivative. WhenA51568A is the starting antibiotic, however, the major product is theN^(leu) derivative. Once again the identity of the product was confirmedby fast-atom-bombardment mass spectrometry. The intermediate Schiff'sbases were not isolated (ni) but a molecular ion is given in all casesfor the reduced alkyl product.

The following compounds were thus prepared:

    ______________________________________                                        Com-                                                                          pound Name                                                                    ______________________________________                                        99    N.sup.van --(n-dodecylidenyl)vancomycin (ni)                             1    N.sup.van --(n-dodecyl)vancomycin, M.sup.+  = 1615                      79    N.sup.van, N.sup.leu --di(n-decylidenyl)vancomycin (ni)                  4    N.sup.van, N.sup.leu --di(n-decyl)vancomycin, M.sup.+  = 1727           55    N.sup.leu --(n-decylidenyl)vancomycin (ni)                               3    N.sup.leu --(n-decyl)vancomycin, M.sup.+  + 1 = 1588                    101   N.sup.van --(n-nonylidenyl)vancomycin (ni)                               5    N.sup.van --(n-nonyl)vancomycin, M.sup.+  = 1573                        80    N.sup.van, N.sup.leu --di(n-nonylidenyl)vancomycin (ni)                  6    N.sup.van, N.sup.leu --di(n-nonyl)vancomycin, M.sup.+  = 1700           102   N.sup.van --(n-octylidenyl)vancomycin (ni)                               7    N.sup.van --(n-octyl)vancomycin, M.sup.+  + 1 = 1560                    81    N.sup.van, N.sup.leu --di(n-octylidenyl)vancomycin (ni)                  9    N.sup.van, N.sup.leu --di(n-octyl)vancomycin, M.sup.+  = 1671           57    N.sup.leu --(n-octylidenyl)vancomycin (ni)                               8    N.sup.leu --(n-octyl)vancomycin, M.sup.+  + 1 = 1560                    103   N.sup.van --(n-heptylidenyl)vancomycin (ni)                             10    N.sup.van --(n-heptyl)vancomycin, M.sup.+  = 1545                       82    N.sup.van, N.sup.leu --di(n-heptylidenyl)vancomycin (ni)                12    N.sup.van, N.sup.leu --di(n-heptyl)vancomycin, M.sup.+  + 1 = 1643      58    N.sup.leu --(n-heptylidenyl)vancomycin (ni)                             11    N.sup.leu --(n-heptyl)vancomycin, M.sup.+  = 1545                       104   N.sup.van --(n-hexylidenyl)vancomycin (ni)                              13    N.sup.van --(n-hexyl)vancomycin, M.sup.+  = 1531                        59    N.sup.leu --(n-hexylidenyl)vancomycin (ni)                              14    N.sup.leu --(n-hexyl)vancomycin, M.sup.+  = 1531                        105   N.sup.van --(n-pentylidenyl)vancomycin (ni)                             15    N.sup.van --(n-pentyl)vancomycin, M.sup.+  1 = 1518                     60    N.sup.leu --(n-pentylidenyl)vancomycin (ni)                             16    N.sup.leu --(n-pentyl)vancomycin, M.sup.+  + 1 = 1727                   106   N.sup.van --(n-butylidenyl)vancomycin (ni)                              17    N.sup.van --(n-butyl)vancomycin, M.sup.+  = 1503                        83    N.sup.van, N.sup.leu --di(n-butylidenyl)vancomycin (ni)                 19    N.sup.van, N.sup.leu --di(n-butyl)vancomycin, M.sup.+  + 1 = 1560       61    N.sup.leu --(n-butylidenyl)vancomycin (ni)                              18    N.sup.leu --(n-butyl)vancomycin, M.sup.+  = 1503                        107   N.sup.van --(n-propylidenyl)vancomycin (ni)                             20    N.sup.van --(n-propyl)vancomycin, M.sup.+  + 1 = 1490                   84    N.sup.van, N.sup.leu --di(n-propylidenyl)vancomycin (ni)                22    N.sup.van, N.sup.leu --di(n-propyl)vancomycin, M.sup.+  + 1 = 1532      62    N.sup.leu --(n-propylidenyl)vancomycin (ni)                             21    N.sup.leu --(n-propyl)vancomycin, M.sup.+  + 1 = 1490                   85    N.sup.van, N.sup.leu --di(ethylidenyl)vancomycin (ni)                   24    N.sup.van, N.sup.leu --diethylvancomycin, M.sup.+  = 1503               63    N.sup.leu --ethylidenylvancomycin (ni)                                  23    N.sup.leu --ethylvancomycin, M.sup.+  = 1475                            28    N.sup.van, N.sup.leu --dimethylvancomycin (64% pure),                         M.sup.+  = 1476                                                         64    N.sup.leu --(n-decylidenyl)-A51568A (ni)                                25    N.sup.leu --(n-decyl)-A51568A, M.sup.+  = 1573                          109   N.sup.van --(n-decylidenyl)-A51568A (ni)                                26    N.sup.van --(n-decyl)-A51568A, M.sup.+  = 1573                          135   N.sup.van --(n-decylidenyl)-M43A (ni)                                   124   N.sup.van --(n-decyl)-M43A, M.sup.+  + 1 = 1616                         122   N.sup.van --(n-undecylidenyl)vancomycin (ni)                            52    N.sup.van --(n-undecyl)vancomycin, M.sup.+  + 1 = 1602                  113   N.sup.van --(3-ethoxy-n-propylidenyl)vancomycin (ni)                    36    N.sup.van --(3-ethoxy-n-propyl)vancomycin, M.sup.+  + 1 =1534           68    N.sup.leu --(3-ethoxy-n-propylidenyl)vancomycin (ni)                    37    N.sup.leu --(3-ethoxy-n-propyl)vancomycin, M.sup.+  + 1 =1534           90    N.sup.van,N.sup.leu --di(3-ethoxy-n-propylidenyl)-                            vancomycin (ni)                                                         38    N.sup.van,N.sup.leu --di(3-ethoxy-n-propyl)-                                  vancomycin, M.sup.+  + 1 = 1619                                         111   N.sup.van --(5-hydroxy-n-pentylidenyl)-                                       vancomycin (ni)                                                         31    N.sup.van --(5-hydroxy-n-pentyl)vancomycin, M.sup.+  = 1533             66    N.sup.leu --(5-hydroxy-n-pentylidenyl)-                                       vancomycin (ni)                                                         32    N.sup.leu --(5-hydroxy-n-pentyl)vancomycin, M.sup.+  = 1533             88    N.sup.van,N.sup.leu --di(5-hydroxy-n-pentylidenyl)-                           vancomycin (ni)                                                         33    N.sup.van,N.sup.leu --di(5-hydroxy-n-pentyl)-                                 vancomycin, M.sup.+  = 1619                                             123   N.sup.van --(3-methylthio-n-propylidenyl)-                                    vancomycin (ni)                                                         53    N.sup.van --(3-methylthio-n-propyl)vancomycin, M.sup.+  = 1536          77    N.sup.leu --(3-methylthio-n-propylidenyl)-                                    vancomycin (ni)                                                         54    N.sup.leu --(3-methylthio-n-propyl)vancomycin, M.sup.+  = 1536          ______________________________________                                    

EXAMPLES 74-109

Similarly prepared were the following reduced compounds. Once again, theintemediate Schiff's bases were not isolated.

    ______________________________________                                        Exam-                                                                         ple No.                                                                       ______________________________________                                        74    N.sup.van --(cyclohexylmethyl)vancomycin, M.sup.+  = 1543               75    N.sup.leu --(cyclohexylmethyl)vancomycin, M.sup.+  = 1543               76    N.sup.van,N.sup.leu --di(cyclohexylmethyl)vancomycin, M.sup.+  =              1639                                                                    77    N.sup.van ( -p-diethylaminobenzyl)vancomycin, M.sup.+  + 1 = 1609       78    N.sup.van ( -p-isopropylbenzyl)vancomycin, M.sup.+  = 1579              79    N.sup.van --(benzyl)vancomycin, M.sup.+  = 1538                         80    N.sup.van --( -p-bromobenzyl)vancomycin, M.sup.+  = 1617                81    N.sup.van --( -p-butylbenzyl)vancomycin, M.sup.+  + 1 =                       1594                                                                    82    N.sup.van,N.sup.leu --( -p-butylbenzyl)vancomycin, M.sup.+  + 1 =             1740                                                                    83    N.sup.van,N.sup.leu --( -p-butoxybenzyl)vancomycin, M.sup.+  =                1771                                                                    84    N.sup.van --( -p-butoxybenzyl)vancomycin, M.sup.+  = 1609               85    N.sup.van --(4-pentylbenzyl)vancomycin, M.sup.+  + 1 = 1608             86    N.sup.van --(4-pentyloxybenzyl)vancomycin, M.sup.+  + 1 = 1624          87    N.sup.van --(pyrrol-2-ylmethyl)vancomycin, M.sup.+  + 1 = 1526          88    N.sup.van --(pyridin-2-ylmethyl)vancomycin, M.sup.+  = 1538             89    N.sup.van --(furan-2-ylmethyl)vancomycin, (poor spectrum)               90    N.sup.van,N.sup.leu --( -p-isopropylbenzyl)vancomycin, M.sup.+  =             1711                                                                    91    N.sup.van --( -p-methylthiobenzyl)vancomycin, M.sup.+  =                      1583                                                                    92    N.sup.van,N.sup.leu --( -p-methylthiobenzyl)vancomycin, M.sup.+  =            1583                                                                    93    N.sup.van --( -p-octylbenzyl)vancomycin M.sup.+  + 1 = 1650             94    N.sup.van --( -p-octyloxybenzyl)vancomycin, M.sup.+  + 1 = 1665         95    N.sup.van --( -p-methoxybenzyl)vancomycin, M.sup.+  + 1 = 1568          96    N.sup.van --(6-nitro-3,4-dimethoxybenzyl)vancomycin, M.sup.+  +               1 = 1642                                                                97    N.sup.leu --(6-nitro-3,4-dimethoxybenzyl)vancomycin, M.sup.+  +               1 = 1642                                                                98    N.sup.leu --( -p-methoxybenzyl)vancomycin (65% pure), M.sup. +  +             1 = 1568                                                                99    N.sup.van,N.sup.leu --( -p-methoxybenzyl)vancomycin, M.sup.+  +               1 = 1668                                                                100   N.sup.van --( .sub.--m-bromobenzyl)vancomycin, M.sup.+  = 1617          101   N.sup.van --( -o-bromobenzyl)vancomycin, M.sup.+  = 1617                102   N.sup.van --( -p-chlorobenzyl)vancomycin, M.sup.+  = 1572               103   N.sup.van --(2,6-dichlorobenzyl)vancomycin, M.sup.+  = 1606             104   N.sup.van --( -p-acetamidobenzyl)vancomycin, M.sup.+  = 1595            105   N.sup.van --( -p-hydroxybenzyl)vancomycin, M.sup.+  = 1553              106   N.sup.leu --( -p-hydroxybenzyl)vancomycin, M.sup.+  =                         1553                                                                    107   N.sup.van,N.sup.leu --( -p-hydroxybenzyl)vancomycin, M.sup.+  =               1659                                                                    108   N.sup.van --( -p-dimethylaminobenzyl)vancomycin, M.sup.30  +                  1 = 1581                                                                109   N.sup.van --( -p-cyanobenzyl)vancomycin, M.sup.+   + 1                  ______________________________________                                              = 1563                                                              

EXAMPLES 110-133

Using the procedure described in Examples 1-2 (with the appropriatestarting aldehyde or ketone), the following compounds can be prepared:

N^(van) -(isopropylidenyl)vancomycin

N^(van) -(isopropyl)vancomycin

N^(leu) -(isopropylidenyl)vancomycin

N^(leu) -(isopropyl)vancomycin

N^(van),N^(leu) -di(isopopylidenyl)vancomycin

N^(van),N^(leu) -di(isopropyl)vancomycin

N^(van),N^(leu) -di(n-decylidenyl)-A51568A

N^(van),N^(leu) -di(n-decyl)-A51568A

N^(van) -(isooctylidenyl)-A51568A

N^(van) -(isooctyl)-A51568A

N^(van) -(n-decylidenyl)-A51568B

N^(van) -(n-decyl)-A51568B

N^(leu) -(n-decylidenyl)-A51568B

N^(leu) -(n-decyl)-A51568B

N^(van) -(n-decylidenyl)-M43D

N^(van) -(n-decyl)-M43D

N^(van) -(benzylidenyl)vancomycin

N^(van) -[3-phenyl-n-(prop-2-enylidenyl)]vancomycin

N^(van) -[(adamant-1-yl)methylidenyl]vancomycin

N^(leu) -(phenethylidenyl)vancomycin

N^(van) -(benzyl)vancomycin

N^(van) -(3-phenyl-n-prop-2-enyl)vancomycin

N^(van) -[(adamant-1-yl)methyl]vancomycin

N^(leu) -phenethylvancomycin

We claim:
 1. A compound of formula (I): ##STR11## wherein R is hydrogenor methyl;n is 1 or 2; and (i) R₁ is hydrogen or methyl; R₂ and R₃,independently, are hydrogen or a group of the formula: R₆ R₇ CH--; R₆and R₇ are independently R₅, R₅ --(C₁ -C₅ -alkyl) or R₅ --(C₂ -C₅-alkenyl); R₅ is hydrogen, C₁ -C₁₀ -alkyl, C₂ -C₁₀ -alkenyl, C₁ -C₄alkoxy, C₃ -C₁₀ -cycloalkyl, C₅ -C₁₂ -cycloalkenyl, phenyl, naphththyl,indenyl, tetralinyl, decalinyl, adamantyl, a monocyclic heterocyclicring system comprising 3 to 8 atoms in the ring or a bicyclicheterocyclic ring system comprising 6 to 11 atoms, provided that atleast one atom of the ring system is carbon and at least one atom of thering system is a heteroatom selected from O, N and S, and R₅ may besubstituted with one or more hydroxy, nitro, C₁ -C₁₀ -alkoxy, C₁ -C₁₀alkyl, phenyl, C₁ -C₆ -alkylthio, nitrile, halo, C₂ -C₄ acylamino,amino, C₁ -C₄ dialkylamino groups; and R₄ is hydrogen; or (ii) R₁ and R₂and/or R₃ and R₄ together form a group of the formula ##STR12## providedthat: (1) at least one of R₂ and R₃ must be other than hydrogen; (2)when n is 2, R must be hydrogen; (3) when R is methyl and R₃ ishydrogen, R₂ cannot be methyl and (4) when R and R₁ are both methyl,then R₂ is hydrogen or methyl and n is 1;or a salt thereof.
 2. Acompound of claim 1 wherein the salt is pharmaceutically acceptable. 3.A compound of claim 1 wherein R₁ and R₂ or R₃ and R₄ together form an R₆R₇ C═ group.
 4. A compound of claim 1 wherein R₂ or R₃ is an R₆ R₇ CH--group.
 5. A compound of claim 4 wherein the group is a C₁ -C₁₂ -alkylgroup.
 6. A compound of claim 5 wherein the group is a C₈ -C₁₀ -alkylgroup.
 7. A compound of claim 6 wherein the group is n-decyl.
 8. Acompound of claim 1 wherein R is methyl.
 9. A compound of claim 8wherein R₂ is an R₆ R₇ CH-- group.
 10. A compound of claim 9 wherein R₃is hydrogen.
 11. A compound of claim 8 wherein R₃ is an R₆ R₇ CH--group.
 12. A compound of claim 11 wherein R₂ is hydrogen.
 13. Thecompound of claim 8 wherein n is 1, R₂ and R₄ are hydrogen and R₃ isn-decyl.
 14. The compound of claim 8 wherein n is 1, R₃ and R₄ arehydrogen and R₃ is benzyl.
 15. The compound of claim 8 wherein n is 1,R₃ and R₄ are hydrogen and R₃ is substituted benzyl.
 16. A compound ofthe formula: ##STR13## wherein R_(2a) is hydrogen or methyl;R_(3a) is R₅--(C₁ -C₆ -alkyl) or R₅ --(C₂ -C₆ -alkenyl); and R_(4a) is hydrogen; orR_(3a) and R_(4a) together form an R₅ --(C₁ -C₆ -alkylidenyl) or R₅--(C₂ -C₆ -alkenylidenyl) group; R₅ is hydrogen, C₁ -C₁₀ -alkyl, C₂ -C₁₀-alkenyl, C₃ -C₁₀ -cycloalkyl, C₅ -C₁₂ -cycloalkenyl, phenyl, napththyl,indenyl, tetralinyl, decalinyl, adamantyl, a monocyclic heterocyclicring system comprising 3 to 8 atoms in the ring or a bicyclicheterocyclic ring system comprising 6 to 11 atoms, provided that atleast one atom of the ring system is carbon and at least one atom of thering system is a heteroatom selected from O, N and S, and R₅ may besubstituted with one or more hydroxy, nitro, C₁ -C₁₀ -alkoxy, C₁ -C₁₀-alkyl, phenyl, C₁ -C₆ -alkylthio, nitrile, halo, C₂ -C₄ -acylamino,amino or C₁ -C₄ -dialkylamino groups;or salt thereof.
 17. A compound asclaimed in claim 1 which is N^(van) -(benzyl)vancomycin; N^(van)-(p-butylbenzyl)vancomycin; N^(van) -(p-butyloxybenzyl)vancomycin;N^(van) -(n-decyl)vancomycin; N^(van) -(p-octylbenzyl)vancomycin; orN^(van) -(p-octyloxybenzyl)vancomycin.
 18. A process for preparing acompound of claim 1 which comprises reacting a compound of the formula##STR14## wherein R_(b), R_(1b) and R_(2b) independently representhydrogen or methyl, and n is 1 or 2, with a ketone or aldehyde offormula: ##STR15## to form an alkylidene or alkenylidene derivative andoptionally reducing this derivative to form an alkyl or alkenylderivative.
 19. A pharmaceutical formulation comprising as an activeingredient an effective antibacterial amount of a compound of claim 2and a pharmaceutically acceptable carrier.
 20. A method for treatingbacterial infections which comprises administering an effective amountof composition of claim 19 to an animal.